Bone is a dynamic tissue whose matrix components are continuously being remodeled to preserve the structural integrity of the skeleton. Bone remodeling is a cyclical process where under normal physiological conditions, bone formation occurs only at sites where bone resorption has previously taken place. Homeostatic remodeling of the skeleton is mediated primarily, if not exclusively, by the osteoclast and the osteoblast (Erlebacher, A., et al. (1995). Cell 80, 371-378). Osteoclasts are giant multinucleated cells of hematopoietic origin that are responsible for bone resorption. Osteoblasts, which originate from mesenchymal stem cells, synthesize the matrix constituents on bone forming surfaces. Proliferation, differentiation and bone remodeling activities of these cells involve a complex temporal network of growth factors, signaling proteins, and transcription factors (Karsenty, G., and Wagner, E. F. (2002). Dev Cell 2, 389-406). Dysregulation of any one component may disrupt the remodeling process and contribute to the pathogenesis of certain skeletal disorders, such as osteoporosis and Paget's disease. Rare single gene disorders resulting in elevated bone mass due to osteoclast defects, collectively termed osteopetrosis, have been identified. Rarer are single gene disorders, exemplified by Camerati-Engelman syndrome, collectively termed osteoschlerosis, in which elevated bone mass is due to intrinsically-elevated osteoblast activity.
Currently available treatments for skeletal disorders and bone loss, whether targeted at bone formation by the osteoblast or bone resorption by the osteoclast, are inadequate. The scarcity of knowledge about the molecular and cellular targets in these cell types hinders the discovery of new therapeutics. Thus, further elucidation of the factors influencing osteoblast activity and/or osteoclast activity would be of value in identifying agents capable of modulating bone formation and mineralization. The identification of such agents and methods of using such agents would be of great benefit in the treatment of disorders that would benefit from increased or decreased bone formation.